Hello everyone, and welcome to Oppenheimer's 34th Annual Healthcare Conference. I'm Jay Olson, one of the biotech analysts at Oppenheimer, and I want to thank you all for joining us here today. It's my pleasure to welcome BioVie to our conference, and it's an honor to introduce Cuong Do, President and CEO. If you have any questions during this presentation, please feel free to submit them using your Q&A function, and we'll try to get to them at the end if there's time for questions. With that, we'll get started. Thank you so much for joining us today, Cuong.
Thank you, Jay, for having me. It's a pleasure to be back. At BioVie, we have two molecules that are currently in the clinic, our lead asset is NE3107, which is a novel inhibitor of inflammation. It reduces inflammation and the associated insulin resistance. In clinical trials, it has shown that Alzheimer's patients treated with 3107 saw improved cognition and function, lower amyloid and p-tau levels, and improved brain imaging scans. For Parkinson's patients, patients treated with 3107 saw improved motor control. In addition, we have seen lower DNA methylation levels, so essentially a modulation of the aging process for these patients. In addition, we have BIV201 in the clinic as well, and we believe this could become the first approved treatment for ascites when it's fully developed. We believe that chronic low-grade inflammation is the starting point for a lot of things going wrong in the body.
TNF-alpha leads to insulin resistance. It drives a pro-inflammatory cycle where additional cytokines, chemokines, and other inflammatory factors are created. It actually drives the phosphorylation of tau in Alzheimer's, and it drives DNA methylation, essentially accelerated aging process. And that's where our molecule comes in. NE3107 is a first-in-class molecule, is a very novel molecule. It's a small molecule, so patients take two capsules, once in the morning and once at night. It was originally brought into the clinic as a diabetes drug before the actual mechanism of action was understood. And once they figured out the mechanism of action, it actually turned out to involve something called ERK, or the extracellular signal-regulated kinase. It's been known for decades that ERK plays two very different roles in virtually every cell in our body. The first involves homeostasis and insulin signaling.
So insulin would bind to cell surface receptors that activate a series of processes that activate ERK for usual cellular growth, repair, and regeneration activities. So this is known as homeostatic ERK. But it's also been well known that ERK plays an important inflammatory role. Various extracellular signals would activate MEK, which in turn activates ERK into its active form called phosphorylated ERK. Phosphorylated ERK would then interact with nuclear factor kappa B through a protein scaffold and trigger the production of TNF-alpha. So this is known as inflammatory ERK. So it's obvious what you want to do. You want to block inflammatory ERK without touching homeostatic ERK. But unfortunately, that's much easier said than done because dozens of teams over decades tried to do it, but they all failed due to toxicity. So could never find a selective enough inhibitor of inflammatory ERK.
That's where 3107 comes in. Frankly, we got lucky. We did not set out to design this molecule. We just got lucky in figuring out how it works. It turns out that 3107 specifically blocks the activation of ERK. Not ERK itself, just simply the activation of inflammatory ERK. Without the activation of ERK, you do not get the activation of NF-kappa B, and therefore you do not get the production of TNF-alpha. Once the team identified this mechanism of action, it became clear to us that NE3107 plays a much, much more important role in Alzheimer's disease. To understand that, I like to start with Alzheimer's pathology. When I first started Alzheimer's research back in the late 1980s, everyone was focused on the amyloid pathway. Here, everything that's blue is a part of the pathway.
Everything that's red is an agent that's trying to modify the pathway in some manner. And we also then started focusing on tau over the decades as well. But the reality is, over the decades of work, not a single agent that reduces plaques and tangles has been identified to also arrest or reverse the cognitive decline in Alzheimer's. And within the last decade or so, I think the research community has warmed up to the idea that plaques and tangles themselves may not be the toxic factor that's leading to neurodegeneration, but in fact, they are inflammatory. They cause neuroinflammation. But the reality is that there are many other factors out there that cause inflammation as well. But they all share one common characteristic. It's that they all activate ERK and NF-kappa B to produce TNF-alpha.
Once you have TNF-alpha, you get the production of more cytokines, which lead to more inflammation. You get the production of more APP, which then feed the production of additional amyloid. TNF-alpha actually drives serine kinases that phosphorylate tau into phospho-tau. Of course, TNF-alpha drives IKK and JNK, which leads to more insulin resistance. Since NE3107 blocks inflammation at the central node right before the production of TNF-alpha, we believe this would be a very different outcome than other Alzheimer's products out there. You may know the work, how Leqembi works. Leqembi has been shown to reduce the amyloid plaque buildup. It has shown only a modest reduction or slowing of cognitive decline.
We believe that's the reason for that is that all that's happened is that you've reduced the inflammatory burden that's driven by the plaques, but you've not done anything about the inflammatory burden that's created by all these other factors here. And 3107 essentially doesn't care where the inflammatory stimuli came from. It blocks it all. So that's why at BioVie acquired this molecule. And when it became part of BioVie, we then took a very aggressive move. We went straight to a phase III, potentially pivotal trial for Alzheimer's without first going back to do a proof of concept phase II trial. If I were still at Merck, or if this were in Merck's hands, Merck would take it back in the clinic to phase II , proof of concept trial to measure the magnitude of therapeutic impact.
With that understanding, you then would go and power two phase III trials for registration. But we're a small, scrappy company. We do not have the resources of Merck, nor did we want to take the extra 2-3 years to kind of go and do that. So we took a very aggressive move of going straight to phase III on the belief that the worst-case scenario is that we would demonstrate the therapeutic impact and miss on stats. In that worst-case scenario, we would be no worse off than playing it safe the way the big pharma would have done it. But if our modeling worked out, we put ourselves in a position to have a phase III win. So that's why we went straight to a phase III trial in mild to moderate Alzheimer's.
We had two co-primary endpoints of CDR-SB, which is the same endpoint that Biogen and Eisai use for Leqembi and donanemab. Then our second co-primary endpoint was ADAS-Cog. We unblinded our phase III, potentially pivotal trial late last year. What we found re-confirmed what we have seen in earlier trials and that 3107 is biologically active. We also found that the cognitive, functional, and biomarker efficacy signals suggest that 3107 has a treatment advantage compared to placebo that is equal to or greater than the results that have been reported in clinical trials for Leqembi and for aducanumab. Furthermore, 3107 is associated with a very benign safety profile. The number one reported adverse event was a mild headache. Unfortunately, we did have a setback. After we unblinded the trial, we discovered that 15 of our sites had significant deviations from Good Clinical Practice.
Therefore, we had questions about the validity of the data from those sites. This should not have happened. I've never seen something like this happen in the United States. We referred all 15 of these sites to the FDA for their investigation. In the meantime, we had to essentially exclude all the data from these sites, which made the data that we have from remaining sites, which showed very encouraging results. While we had encouraging results, we missed of statistical significance. We will have to come back and address that in another trial. Let me share with you what we found as we unblinded.
So among the sites where we did not have to exclude on our primary endpoint of CDR-SB, what we found is that 3107 treated patients had an advantage compared to placebo equivalent to a 68% slowing of cognitive decline compared to placebo. And to put this into context, we achieved 68% slowing of cognitive decline compared to placebo after 6 months of treatment compared to lecanemab, showing a 27% slowing of decline after 18 months of treatment. So this is not meant as a head-to-head comparison, which can only be done in a single head-to-head trial, but this is only meant to share with you the magnitude of the impact that we're seeing. But unfortunately, we missed on stats. We have trending data here.
If we did not have to exclude all those patients, I am positive that we would have missed on stats to demonstrate this significant slowing of cognitive decline. If you look at all of the other cognitive and functional measures, you see that 3107 had an advantage compared to placebo that is equal to or greater than the advantage that has been shown in clinical trials for the comparative drugs. We also looked at a number of biomarkers. What we found is that the improvement in CDR-SB, or so the improvement in cognition, is correlated to the improvements in inflammation, reduction of TNF-alpha, correlated to reduction of phospho-tau, and correlated to the reduction of the amyloid burden. We also looked at two additional neurodegeneration biomarkers, neurofilament light and GFAP.
Since these are biomarkers of neurodegeneration, as neurodegeneration increases, as evidenced as shown here by worsening cognition, you see a very significant correlation between the worsening of cognition and the increase in the release of the biomarkers in the placebo groups. You see these very significant correlations. But for those that are treated with 3107, 3107 just shuts down the release of those biomarkers altogether. We believe that reducing the neuroinflammatory processes leads to this significant change in the correlations of how these biomarkers work. Our advisory boards are very intrigued by this. We're still trying, frankly, to really understand how this works. So we're continuing to work with our advisors on that. And we're looking forward to exploring it further in the future trials. In the same trial, we also saw some additional data in our work in longevity and aging.
To explain this, I like to start by giving an example. If you think about a DVD, when you have a new, pristine DVD that you just took out of the box and put it into the player, the laser has no problem decoding what's contained on that disc. As a result, you get beautiful sounds and pictures. But as you play that disc over and over again over the years, you'll get scratches, you'll get fingerprint smudges on it. As a result, you'll get blurrings, skipping, and so forth. As it turns out, the same thing happens in our bodies. Everything in our body, as you know, is encoded before by our DNA and our genes. As we age, a natural process called DNA methylation takes place, whereby different methyl groups get added to our DNA at various locations.
We know that DNA methylation naturally increases as we age. We also know that DNA methylation is affected by our behavior on things like diet and exercise as well as our environment. We know that DNA hypermethylation is associated with a large number of diseases out there, especially age-related conditions. We know that inflammation, TNF-alpha, is a key driver of hypermethylation for DNA in how it drives an enzyme called DNA methyltransferase 3A and B. The extent of DNA methylation can be measured by various clocks. In the phase III trial for Alzheimer's, we took blood samples from the patients at the end of the trial, and we sent it to Steve Horvath's team at UCLA, who's the guru when it comes to DNA methylation and the inventor of something called the Skin & Blood Clock, which is the leading clock that's used in this arena.
What we found is that patients treated with NE3107 saw a 4+ years advantage in age deceleration compared to those who are treated with placebo. What this means is that there was an advantage in lower DNA methylation levels for those that are treated with NE3107, as measured by the Skin & Blood Clock. Age deceleration is simply the difference between your biological age as measured by the Skin & Blood Clock compared to your actual chronological age. So a 4-year advantage in reduction of DNA methylation is a huge deal. And we also saw that the reduction of age deceleration is correlated to the improvement in cognition that was observed in the trial. So in totality, when you look at this data, when we look at this data, we are very encouraged by the data, the directional data that the sites show us here that we're not excluded.
Unfortunately, because we had to exclude those 15 sites, it really hurts because we missed on stats. We are now meeting with the FDA this quarter and then deciding on what course to go forward on how to essentially either resume enrolling patients for this trial or to redo the trial altogether. Let me turn now to talk about our work in Parkinson's disease. We conducted a phase II trial in Parkinson's disease. What we did was what we saw is after 28 days of treatment, those patients that were treated with 3107 and levodopa, which is a standard of care as shown in blue here, saw a 3+ point advantage compared to those who were treated with just levodopa alone as shown in red.
A 3-point advantage is a clinically meaningful advantage as measured by something called the Part III or the motor score of the Unified Parkinson's Disease Rating Scale. If you look at patients who are younger than 70 years old, presumably because their Parkinson's has not advanced to the most severe form, the advantage is over 6 points. But what got us and our experts really excited has to do with what's called the morning-on symptoms at time zero. Now, it's well known that levodopa has a short half-life. So that when Parkinson's patients wake up in the morning, they often find that their levodopa has worn off overnight. And in our trial, none of the patients that were treated with just levodopa alone had their muscles in the on-mode, meaning that they could move their muscles and get out of bed. None essentially could do so.
Whereas roughly a third of these patients that were treated with 3107 and levodopa saw that they had motor control, had the significant advantage compared to just levodopa alone, and they could get out of bed in the morning. This was a significant finding here. Our experts were very excited about this finding, and they basically advised us to change the way that we were developing the drug. We originally did this trial believing that 3107 should be given in conjunction with levodopa for the moderate and most severe patients out there. Seeing that this morning-on symptom here, they basically told us this is the biggest unmet need in Parkinson's right now. Given the preclinical signals of being able to delay neurodegeneration, they're basically urging us to develop 3107 as monotherapy, as first-line therapy. That's what we're going to do.
Later on this summer, we'll be launching that trial as well as to develop 3107 as monotherapy and as first-line therapy for patients who have been diagnosed, who now need to go on to medications for the first time. So being mindful of the time, let me just very quickly turn to our work in liver disease. Ascites is a condition that's late-stage liver disease. When it gets to this point, the liver has been very damaged and scarred such that it's not able to process fluid as it normally does. So the fluid accumulates in the abdomen. And eventually, all you can really do is stick a large bore needle to evacuate the fluid physically. And because there's no approved drug for ascites.
So when these patients do get some initial relief, but since nothing has been done to address why the fluid accumulates to begin with, these patients are constantly coming back to the hospital or emergency room every week or 2 to get another 5-10 liters of fluid removed. And you can imagine the stress that puts onto the body. So our drug is a new formulation of a drug called terlipressin. We put it into an IV bag, hook it up to a portable continuous infusion pump that patients wear on their belt. And then we infuse the drug in over the course of the day. We had a phase II-B trial underway aiming to enroll 30 patients. And we stopped this trial early.
Because midway through the trial, we had statistically significant data showing that those that were treated with BIV201 saw an over 50% reduction in the ascites volume buildup compared to practically no change for the standard of care. This was a very statistically significant finding. So given the large unmet need in this condition, we believe that the only reasonable thing to do was to stop the trial early and to engage the FDA in the conversation on how to move this thing into phase III. And we have received the feedback from the FDA to allow us to design the final phase III protocol to take this thing into the trial. Since we already have orphan and fast-track designation, we only need one trial to get this thing registered. So with that, let me stop here to see if Jay and anybody else has any questions. Thank you for your time.
Mark, thank you very much for that comprehensive overview and all the work that you're doing at BioVie. Appreciate the update. Maybe just to start off with going back to your Alzheimer's program, can you just talk about any feedback that you've received from physicians, investigators, any initial comments from the FDA that you could share with us? I know you said you're meeting with them this quarter, but have you had any initial dialogue?
We have not had initial dialogues with the FDA. The only dialogue we have had so far involved us referring the 15 sites onto the FDA for their investigation. This magnitude, this level of deviations from our protocol and our GCP, I sometimes have seen it abroad in India and so forth, but I've never seen this magnitude in the U.S. So they are taking it very seriously. The experts that we have spoken to are very encouraged with this level of directionality in the data. Our statisticians, our statistical experts would basically say, if you look at the degree of data variability and so forth, we're very confident that if we had the 125 patients in each arm that we had planned the study was powered to produce, we would have been able to achieve statistical significance here.
So that's why we are now either going to continue enrolling patients into this trial because we have an adaptive design in place, or frankly, we're just going to redo the study. And I am personally leaning towards just redoing the trial altogether. Because this trial was started two and a half years ago when we did not have as much data on the molecule and frankly, it started enrolling during the heights of COVID. Now that we have a much better understanding of how the molecule works and what the magnitude is, I think if we just redid the trial, we could make it a much simpler trial that's easier to execute, and we could do it much faster as well.
Okay, understood. I guess one of the questions that we get is related to a possible collaboration strategy. Is there an opportunity to seek, for example, a grant or a partnership with a research institute that could help you rerun the study?
Well, we have been in discussions with a number of pharma companies who have been intrigued by this molecule. Frankly, they all have been waiting for the results of this trial. Unfortunately, because we missed on stats, our large pharma companies basically are just continuing to wait, as I said, on the sidelines. Hey, I was from Big Pharma. I've been on their side of the table as well. I can totally understand where they're coming from, given the graveyard of failed molecules in this particular arena. I think for the time being, large pharma is taking a wait and see. We have a number of midsize pharma that we're currently talking to as well for different geographic or regional rights to collaborate with us.
We have applied for a number of grants that we hope to be able to give some guidance and disclosures in the coming months. Not only in Alzheimer's and Parkinson's, but in additional indications as well because we believe that 3107 has applicability in a number of other indications that are all information-driven.
Okay, great. And then I guess shifting gears over to Parkinson's disease, thank you for the update on that program. Similar line of questioning, what are the next steps and is there a potential collaboration in the works there?
We are talking to a company right now about potentially collaborating on this. Again, it's a midsize company. This trial, we've been working on this trial now for months, many, many months, getting it ready. So we have the sites, the investigators, the CROs pretty much lined up. And the only thing that we're doing right now is we are finalizing funding for it, finalizing, crossing the i's, dotting the i's, crossing the t's, and just making sure everything's in place so that we hope to launch this trial later on this summer.
Okay, great. We'll look forward to that. And then I guess lastly, on your ascites program, you've got positive phase II data in hand. I know you said you're talking to the FDA. Can you just outline just to set investor expectations, what's the timeline for initiating and running a phase III study and how soon can you file and get approval?
Sure. The FDA gave us very, very helpful feedback on this. I think the way that we are going to conduct this trial is that we're going to look at helping prevent complications for cirrhotic patients. The guidance that we've heard from our advisors and everyone else is take it earlier in the disease progression so that we can actually demonstrate a much greater impact. We look forward to essentially sharing much more about this protocol. What we believe is that we can take this earlier into the condition. At the moment that a patient has an acute kidney injury resulting from cirrhosis, you know that that patient is going to be having a repeat AKI. We believe we can reduce and prevent that repeat, which makes this a very, very simple trial to conduct.
And then the other thing, the very, very great conversation with the FDA is that we were able to move them from requiring a placebo-controlled trial because this is administered through continuous infusion, so you have to put in place a PICC line. So we thought it was unethical to essentially put in a PICC line for those that are still on standard of care getting placebo. So this is going to be an open-label trial where we're going to randomize patient to standard of care and drug and then just see how we're able to reduce the complications post the first AKI or the first complication. And so we believe this is going to be a small trial. It could be done relatively quickly. And we're going to start it when we finalize plans for our partner and have the partner fund the trial with us.
Okay, understood. And we've got a few questions coming in from the audience. Just going back to Alzheimer's for a second. Can you just share with us the sort of questions that you'll be asking the FDA when you meet with them? What's the timeline for starting a new trial? And we have a question asking about what are the CRO's responsibilities here? Do they owe you another phase III trial and how will that work?
Well, we had been planning for another phase III trial, as you know, before we even unblinded this phase III trial. So we had lined up another CRO to help us on a global basis because this trial was only U.S.-only, focused on the U.S. We needed a global trial. So we had lined up another CRO to help us in the U.S., Europe, and Australia. So we had another CRO already lined up. And the conversations that we are having with the FDA is that we are submitting our CSR, CRS, our clinical study report relatively soon, and we're hoping to be meeting with them in March. Our primary conversation really has to do with verifying primary and secondary endpoints because we know much more about the endpoints right now. And as you know, the FDA right now only recognizes one biomarker in Alzheimer's disease.
That's the amyloid burden. We believe that we will be able to demonstrate an impact on phospho-tau in addition to amyloid beta. We think we can demonstrate an impact at NfL and GFAP as well. Our real conversation is about how do we think about using these additional biomarkers that have been widely discussed out there? And how can we use that as part of our trial?
Okay, great. And the timeline and the.
Timeline, that this frankly, this is somewhat cash-dependent. So it's funding-dependent. So we will start this trial once we've raised the funding for it. My guess is we will probably delay this trial until after the Parkinson's trial has been started, well underway.
Okay. This might be a legal question, but any liability on behalf of the CRO?
Well, as you know, we've referred everything onto the FDA to investigate. Everyone wants me to go and litigate and sue everybody involved. I'm just not going to do that. I think the prudent thing to do right now is let the FDA conduct their investigation because they have far more investigatory power than we do. Upon that result, we then will go and explore all the recourse that's available to us.
Okay, perfect. Well, that brings us to the end of our time. Thank you so much, Cuong. It's great catching up with you. Really appreciate your bringing us up to speed on all the work you're doing at BioVie, and we'll look forward to future updates.
All right. Thank you, Jay. Thank you for having me with you today.
Our pleasure. Thanks, Cuong. Thanks, everyone.